This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The activation of AKT (also known as protein kinase B), a serine/theronine protein kinase plays an important role in many signal transduction pathways. Hyperactivation of AKT leads to malfunctioning of cells and various diseases. There are three isoforms of AKT. Each AKT member contains an N-terminal pleckstrin homology (PH) domain, a linker region, a short alpha-helical linker, a C-terminal kinase domain and a regulatory domain. In the early steps of activation process of AKT, PI3K-generated D3-phosphorylated phosphoinositides (phosphatidylinositol-3,4,5-triphosphate (PIP3)) bind the AKT PH domain and induce the translocation of the kinase to the plasma membrane. Crystal structures exists for the separate domains of AKT2, but not the entire AKT. We have build a three-dimensional structure of AKT in both its active and in-active states spanning the entire PH, kinase and regulatory domains which satisfy the inter-domain interactions known through biochemical experiments. CHARMM (Chemistry at HARvard Molecular Mechanics) is a general simulation package used to study protein and nucleic acid structure and function. We propose to use CHARMM22 force field to model the energetics, forces and dynamics of AKT structure using the classical method of integrating Newtons equation of motion using version c32b1. We will use the required 30,000 SUs to run 5 ns Langevin dynamics simulations each in CHARMM using GBSW implicit membrane model of the two structures to study AKT structure-function relationships relevant to AKT hyperactivation by addressing following questions: a) What is the structural and dynamical basis of structure-activity relationship in AKT. b) How intra-domain conformational changes are transmitted across the structure leading to inter-domain structural perturbations which form an integral part of activity of AKT.